The motor cortex of all mammalian species, including humans, contains a gross somatotopic representation of the major divisions of the body, such as hindlimb, forelimb, and face. Within each body part, there are multiple, non-contiguous, partially overlapping representations of individual movement patterns. Thus, the motor cortex is comprised of a distributed network in which specific movements emerge from broad patterns of activity. The neural mechanisms that sculpt voluntary movements from these dynamic networks are unknown. Our goal is to narrow this fundamental gap in our knowledge by identifying mechanisms that dynamically regulate the organization of cortical motor networks during voluntary movements. During movement execution, proprioceptive and tactile sensors provide continual inputs that guide the movements. There is compelling evidence that these somatosensory inputs act upon motor cortical networks to dynamically regulate their outputs. Based on our preliminary findings in rats, and on studies in humans, we propose that somatosensory afferents regulate motor cortical activity in a center-surround manner: Somatosensory stimuli from an activated muscle enhance cortical outputs to that muscle ("center-excitation"), whereas cortical outputs to adjacent muscles are suppressed ("surround- inhibition"). We test this hypothesis in Aim I. Somatosensory inputs reach the motor cortex through two major pathways: thalamocortical afferents from the ventral lateral thalami nucleus (VL), and corticocortical afferents from the somatosensory cortex (SCx). We propose that thalamic inputs provide the substrate for extensive feed-forward inhibition in motor cortex. By contrast, the specificity of corticocortical inputs suggests that they are involved in center- excitation - enhancing motor cortical outputs to the muscle providing somatosensory inputs. We will directly test this hypothesis in Aim II. How do somatosensory afferents differentially impact homotypical versus heterotypical cortical modules? We propose that somatosensory afferents exert a net inhibition of motor cortical circuits, such that only `strong'afferent inputs-occurring in response to converging inputs from VL and SCx-overcome this inhibition to activate homotypical motor cortical neurons. As a result, inputs arising from a limb in motion converge upon and excite cortical modules that activate that limb, while feed-forward inhibition dominates inputs to neighboring modules. We will test this hypothesis in Aim III. PUBLIC HEALTH RELEVANCE: The execution of voluntary movements relies on coordination among cortical motor neurons. Thus, the anticipated findings address principles fundamental to motor control. An immediate practical application of the anticipated findings is in the field of neuroprosthetic controllers, which couple neuronal signals from motor cortex with robotic devices. In addition, a number of neurological disturbances are associated with deficits in interactions among cortical motor modules. These include motor cortical infarcts, dystonia, and disorders of the basal ganglia. Knowledge of the mechanisms coordinating motor cortical modules is thus critical to the understanding and improved treatment of a wide range of motor disturbances.